Understanding the Puzzling Pathology of COVID-19

Andrew N. Wilner, MD; William W. Li, MD


June 04, 2020

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This transcript has been edited for clarity.

Andrew N. Wilner, MD: Welcome to Medscape. I'm Dr Andrew Wilner, and today I have the pleasure of speaking with Dr William Li, president and medical director of the Angiogenesis Foundation. Welcome, Dr Li.

William W. Li, MD: Thank you, Dr Wilner. It's a pleasure to be here.

Wilner: Thanks for joining us. I saw that you are one of the coauthors of a paper this month in the New England Journal of Medicine that has to do with angiogenesis and COVID-19. This is a pretty hot topic. Because you're one of the authors, you know more about it than anybody else. I'm glad to have you here to speak with us. So tell us about the paper. What did you find?

Li: When the COVID-19 pandemic hit, I, like many scientists, immediately started to pivot from whatever we were doing at the time to trying to tackle this enigma which, in 200,000 years of human history, humans have never encountered.

There's been so much confusion and some misinformation. I think that this is where medical science really steps in to take command and control, because while we don't know everything about SARS-CoV-2 and COVID-19, every layer of the onion we peel back gives us an additional piton on a rock wall to understanding this disease.

In modern medicine, that's what we really try to do. Before we can develop effective treatments, we really need to understand the pathophysiology.

As a vascular biologist, I teamed up with my colleagues who study pathology and angiogenesis, the microcirculation, to ask what is actually happening in the lungs of these people who are infected with COVID-19. We felt that to get at the answer, we'd start at the end to understand that beginning.

We were able to obtain autopsy tissue from people who died of COVID-19 and compare their lungs with those from people who had died almost 20 years ago from the SARS-CoV-1 pandemic.

We also looked at H1N1 and at normal lungs donated by people who were providing tissue for lung transplants. We started to do a deep dive to look at what was actually happening. What we found and reported in the New England Journal Medicine was really interesting because this respiratory virus, which we breathe in, does get down to our pulmonary tree. It does cause respiratory infections, so we saw intense inflammation and the acute respiratory distress syndrome pathologic signs.

We also found something surprising, which is that this respiratory virus makes a beeline for the vascular, or endothelial, cells, where gas exchange takes place. As the vascular cells and endothelium are infected, it damages them.

We actually saw the damaged cell membranes using transmission electron microscopy. This was directly associated with the microthrombi, which we've now recognized to be a hallmark of COVID-19—not in every patient, but in many patients that winds up becoming a significant problem.

As we dove deeper, we realized that this respiratory virus actually causes a vascular disease as well as a pulmonary disease. We then dove deeper to really ask what is happening at the gene-expression level. How do the blood vessels respond to it, which actually is a form of new blood vessel growth, a kind of an emergency response or panic response to microthrombi.

We speculated that if this is happening in the lung, could it be happening in other organs of the body as well?—yielding some explanation for some of these other vexing clinical signs that we've seen in COVID-19.

Wilner: That was a great explanation. First of all, I read the paper just before we started this interview, and it is a fantastic paper. It is clear. I love the images. It brought back memories of when I was on my pathology rotation in medical school, and I could actually understand it! I read all these papers and they have an image and there's different blue and red and green—I never know what they are, but these images were very clear.

I've spent a lot of time recently trying to understand the neurologic complications [of COVID-19]. A big question has been, is this virus neurotrophic? In fact, there's an article that I wrote a couple of weeks ago that's on Medscape that reviews all of this.

My conclusion was that it doesn't seem to be, but one of the thorny points was, how come so many patients are having strokes? At first we said it's because they're old, sick, they're in the ICU, and they're going to have strokes. But then there have been reports of young, otherwise healthy patients having strokes.

It looks like you may have the explanation: that there is a hypercoagulable state because of damage to the blood vessels that causes not only lung but also vascular disease in the brain and causes strokes. What do you think?

Li: Well, our paper focused on the lung as a starting point, but I think it opens the door to future investigations, which we're actually in the middle of right now ourselves. We are looking at brain. Within a few weeks, we should have the first detailed comparison of whether or not the endothelium is similarly infected and injured in the people who actually died of stroke.

We actually are interested in comparing COVID-19 stroke with other forms of stroke—ischemic stroke, or classic strokes—to look for those differences. Stay tuned for that.

I think that the other issue is that if this is a vascular disease that could be extrapolated from the lungs throughout the body, is this also happening within the myocardium? We are actually getting capillary endothelialitis within the heart muscle, within brain tissue, and maybe even within peripheral nerve as well.

An interesting finding is COVID toe, which has actually been the presenting sign in people who don't have a cough or fever, and they go to their podiatrist or vascular surgeon with this beefy red toe and a lot of pain. It turns out that later on they test positive for the SARS-CoV-2 virus.

Are we looking at a systemic vasculitic type of syndrome that can affect everything from the toe to the brain? If we are, how do we understand, number one, how the virus transmits from the lung to those distal organs? Are they circulating and disseminating as an infection or are they actually finding another way to crawl cell to cell and Tarzan-ing their way into our organs?

Once they get to those organs, how do they cause damage? Why don't they cause damage in every patient? How much is actually due to coagulopathy versus other potential effects? Don't forget, the coagulopathy is on the inward-facing side of endothelial cells to the blood. Endothelial cells have two sides, including the abluminal side, or the side that actually faces the tissue.

When I started to look at some of the neurologic manifestations of COVID-19, I noticed that there were some patients who presented with bilateral encephalitis. I started to wonder how that works, because that's not a classic ischemic stroke.

You would be a much better judge of this than I would, but as an internist, I started thinking, how many things go to both sides of the brain? And why would that actually happen? Are there telltale clinical symptoms or signs that might allow us to actually do early detection, early diagnosis of people who might be more vulnerable or might go on to develop more serious neurologic symptoms?

Wilner: Let's jump to the ICU, where we have patients with COVID. Should they be anticoagulated?

Li: A really important paper came out in the Journal of the American College of Cardiology just a couple of weeks before our paper, looking at patients who had been hospitalized and discharged or expired, and looking at their coagulation or anticoagulation status.

It was pretty clear from that study—Dr Valentin Fuster, a colleague of mine, was one of the coauthors of that paper—that those patients who were anticoagulated actually had a better outcome or higher rate of discharge from the hospital. Now, that's not necessarily a cause and effect, but it's a pretty compelling association if you take a look at the fact that these microthromboses could be happening not only in the lung but everywhere in the body.

I think an even bigger question would be, if you test positive and you're not hospitalized, should you be discharged from the emergency room home with anticoagulation? Would that be something we should be doing? Should you be on low-molecular-weight heparin? Should you be on aspirin? How should you be monitored post discharge home?

Are there other ways that we should be doing follow-up on these patients other than the classic "You're not sick enough with an infectious disease to be hospitalized; let’s send you home"? Maybe in some of the people who go home and then drop a few weeks later, there is a propagating coagulopathy that really could have been managed from the time of sending them home from the emergency room.

Wilner: Maybe after a positive COVID test, you need a D-dimer test or some other assessment of coagulation to see if you're high-risk in at least a moment in time.

Now, let's just turn this upside down a little bit. One of the things you've told us is that this virus causes the blood vessels to react and actually increases angiogenesis. Could that ever be a good thing?

Li: Right. Don't forget, this is an autopsy study. This is not a real-time study. Think of it as a crime scene investigation; we're collecting the clues and trying to put together the pieces of what's happening.

One of the things that we did see that was surprising is that the blood vessels that had thrombi actually underwent a reactive form of angiogenesis, new blood vessel growth. That type of reactive angiogenesis was different from the regular sprouting that you would see in the heart, in wounds that are healing, and granulation tissue. Even following a typical ischemic stroke, you wind up getting some sprouting angiogenesis around these focal points of ischemia.

Here, what we saw is a different form of angiogenesis called intussusception. Now, this is not the pediatric intussusception where you think about the intestines. This is a form where a single blood vessel divides into two blood vessels by actually dropping drywall in and splitting into two.

Think about what this means. Why is it a reactive form? When you actually have all these microthrombi occurring everywhere, you don't have time for the 2 or 3 days it takes to sprout. You need immediate splitting in an effort to deliver better blood flow.

Now think about yourself as a car driving in a one-lane tunnel. Your car is an erythrocyte, and you're driving in a one-lane tunnel and the blood vessel is trying to react, and it drops drywall in from the ceiling to the floor. Where is the car going to go? You suddenly have turbulent blood flow in this emergency reactive form of angiogenesis, which probably contributes to the thrombotic setting in the context of endothelial damage.

The third strike for coagulopathy is really this intense inflammatory response. We saw tons of T cells wrapped around these thrombotic, reactive, angiogenic small blood vessels, and that makes total sense. The T cells are trying to clear the virus from the endothelial cells, but our normal circulation is in the way.

These were three smoking guns that we saw that might help us understand the microthrombosis, leading us to ask what is happening in other organs. That's really where we are today—taking this crime scene investigation into the heart, into the brain, into the toes, into the kidneys, and into other organ systems so we can really try to put together a more systemic view of the role of endothelialitis and angiogenesis in COVID-19.

Wilner: Dr Li, this has been a fantastic illumination of what is happening inside the human body with COVID-19. I think it's also a message to all of those who think it's okay to give up social distancing. I think it's a reinforcement to say, hey, you don't want to get COVID-19 now. Why don't you keep social distancing, wear that mask, keep 6 feet away, and don't get the disease.

In 6 months or a year, we may understand this disease well enough that we will have a therapy. You don't want to be sick in the ICU or—worse—next weekend when we're both on call, right? I think this is really great.

Li: One concluding point that I will tell you that this raises a specter upon is that after the virus is cleared from the body, after one has recovered from the SARS-CoV-2 virus, we don't know yet what the long-term damage is that may occur and may persist in the vascular endothelium. If it turns out that there was widespread systemic damage to endothelial cells, then that could persist much longer than the actual infectious component of the virus.

I think that one of the red flags that got sent up as we looked at this is to ask the question in long-term survivors of COVID-19, of which there will be many because this virus doesn't kill most people. It kills some, but many people actually recover. What might be the long-term manifestations of this novel coronavirus? I think time will tell, but this is where medical research is just beginning to chip away at the enigma of COVID-19.

Wilner: Where can people find more information about the Angiogenesis Foundation?

Li: You can find out about the Angiogenesis Foundation on our website at www.angio.org or you can find me pretty easily on the Internet at drwilliamli.com.

I've also written a book called Eat to Beat Disease. There's quite a lot of interest in this because I'm also interested in the impact of healthy lifestyles and diet on endothelial health.

Wilner: That's great. Thank you very much for joining us on Medscape, Dr Li. I look forward to your next set of discoveries.

Li: Thank you, Dr Wilner.

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